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Open Access Research article

Clinical and molecular characterization of a transmitted reciprocal translocation t(1;12)(p32.1;q21.3) in a family co-segregating with mental retardation, language delay, and microcephaly

Hsiao-Mei Liao1, Jye-Siung Fang2, Yann-Jang Chen34, Kuang-Lun Wu5, Kuei-Fang Lee6 and Chia-Hsiang Chen567*

Author Affiliations

1 Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan

2 Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan

3 Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan

4 Department of Teaching and Research, Taipei City Hospital, Taipei, Taiwan

5 Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan

6 Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan

7 Department of Psychiatry, Chang Gung Memorial Hospital at Linkou and Chang Gung University School of Medicine, Taoyuan, Taiwan

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BMC Medical Genetics 2011, 12:70  doi:10.1186/1471-2350-12-70

Published: 20 May 2011

Abstract

Background

Chromosome translocation associated with neurodevelopmental disorders provides an opportunity to identify new disease-associated genes and gain new insight into their function. During chromosome analysis, we identified a reciprocal translocation between chromosomes 1p and 12q, t(1; 12)(p32.1; q21.3), co-segregating with microcephaly, language delay, and severe psychomotor retardation in a mother and her two affected boys.

Methods

Fluorescence in situ hybridization (FISH), long-range PCR, and direct sequencing were used to map the breakpoints on chromosomes 1p and 12q. A reporter gene assay was conducted in human neuroblastoma (SKNSH) and Chinese hamster ovary (CHO) cell lines to assess the functional implication of the fusion sequences between chromosomes 12 and 1.

Results

We determined both breakpoints at the nucleotide level. Neither breakpoint disrupted any known gene directly. The breakpoint on chromosome 1p was located amid a gene-poor region of ~ 1.1 Mb, while the breakpoint on chromosome 12q was located ~ 3.4 kb downstream of the ALX1 gene, a homeobox gene. In the reporter gene assay, we discovered that the fusion sequences construct between chromosomes 12 and 1 had a ~ 1.5 to 2-fold increased reporter gene activity compared with the corresponding normal chromosome 12 sequences construct.

Conclusion

Our findings imply that the translocation may enhance the expression of the ALX1 gene via the position effect and result in the clinical symptoms of this family. Our findings may also expand the clinical phenotype spectrum of ALX1-related human diseases as loss of the ALX1 function was recently reported to result in abnormal craniofacial development.